Graft Monocytic Myeloid-Derived Suppressor Cell Content Predicts the Risk of Acute Graft-versus-Host Disease after Allogeneic Transplantation of Granulocyte.

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Graft Monocytic Myeloid-Derived Suppressor Cell Content Predicts the Risk of Acute Graft-versus-Host Disease after Allogeneic Transplantation of Granulocyte Colony- Stimulating Factor–Mobilized Peripheral Blood Stem Cells Antonio Vendramin, Silvia Gimondi, Anisa Bermema, Paolo Longoni, Sara Rizzitano, Paolo Corradini, Cristiana Carniti Biology of Blood and Marrow Transplantation Volume 20, Issue 12, Pages 2049-2055 (December 2014) DOI: 10.1016/j.bbmt.2014.09.011 Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 G-CSF treatment of HSCT donors induces an increase in the frequencies of circulating M-MDSCs in respect to healthy nontreated volunteers as assessed by flow cytometric evaluation of Linlow/neg HLA-DR− CD11b+ CD33+ CD14+ (P = .0002). Bars represent median values, whereas whiskers represent minimum and maximum. Biology of Blood and Marrow Transplantation 2014 20, 2049-2055DOI: (10.1016/j.bbmt.2014.09.011) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 In vitro co-culture of immunomagnetic selected CD3 T lymphocytes isolated from peripheral blood of HSCT donors and M-MDSCs selected through a double-step immunomagnetic separation. PBSC graft cells were first depleted of HLA-DR+ cells, and thereafter myeloid cells expressing the CD33 antigen were enriched through positive selection. Purity of all populations was assessed by flow cytometry, demonstrating an efficiency of separation of more than 90% in all experiments. CD3+ lymphocytes were stimulated with CD2/CD3/CD28 microbeads with or without different ratios of M-MDSCs (1:1 or 1:5). Cells were also plated without microbeads as negative control. Immunosuppressive properties of M-MDSCs were assessed by flow cytometric analysis of the surface activation markers CD25 and CD137. Co-culture experiments demonstrate the ability M-MDSCs to suppress T cell activation in a dose-dependent manner on both CD4+ helper T cells and CD8+ cytotoxic T cells. Experiments were carried out in triplicate. Biology of Blood and Marrow Transplantation 2014 20, 2049-2055DOI: (10.1016/j.bbmt.2014.09.011) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Probabilities of aGVHD were calculated with the cumulative incidence procedure, with relapse and death without aGVHD within 180 days as competing events (48%). Biology of Blood and Marrow Transplantation 2014 20, 2049-2055DOI: (10.1016/j.bbmt.2014.09.011) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Box plots showing the absolute number of infused M-MDSCs with respect to aGVHD. Significantly lower quantity of M-MDSC/kg body weight were infused in patients who developed aGVHD with respect to those who did not (median 28.5 × 106/kg versus 49.4 × 106/kg total CD45+ cells, Mann-Whitney t-test P = .02). Bars represent median values, whereas whiskers represent minimum and maximum. Biology of Blood and Marrow Transplantation 2014 20, 2049-2055DOI: (10.1016/j.bbmt.2014.09.011) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Cumulative incidence of aGVHD at 180 days after unrelated HSCT in patients receiving below (solid line) versus above (dashed line) the median dose of M-MDSCs (64% and 22%, respectively, Gray's test P = .02). Biology of Blood and Marrow Transplantation 2014 20, 2049-2055DOI: (10.1016/j.bbmt.2014.09.011) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 The dose of 37 × 106 M-MDSC/kg body weight is associated with the best combination of sensitivity and specificity. Receiver-operating characteristic curve displaying the false-positive rate versus the true-positive rate for every possible dose of M-MDSCs infused (area under the curve [AUC] .71). Biology of Blood and Marrow Transplantation 2014 20, 2049-2055DOI: (10.1016/j.bbmt.2014.09.011) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions